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Author: Subject: Preparation of Thalidomide
Tsjerk
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[*] posted on 9-1-2022 at 10:49


Definitely get some DMF to recrystallize when you go the glutamic acid route.

[Edited on 9-1-2022 by Tsjerk]
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[*] posted on 9-1-2022 at 13:43


Yes, there is an ongoing research for the needed reagents. I live in one of the most repressive countries on the planet when it comes to odd hobbies of suspicious nature, so it will take a while.
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[*] posted on 22-10-2022 at 13:22


So finally I got around to do this.

I thought I'd combine the two methods in the write-ups above with the best yields: pyridine as solvent in the first step (with glutamic acid and phtalic anhydride), and thiourea + DMF in the second.

I purchased the first reagent, phtalic anhydride, from a seller in Ukraine before the war. The glutamic acid I made myself from commercial Monosodium Glutamate. I also made the pyridine through decarboxylation of niacin with copper carbonate as catalyst. The DMF and the thiourea were both purchased from one of the excellent vendors on this site.

1. 14.95 grams of phtalic anhydride in the form of flaky crystals was mixed with the same amount of glutamic acid in a 3-necked RB fitted with a thermometer and a reflux column. 100 ml of pyridine was added.
And already here I messed up. I had measured up 100 ml of conc HCl and 150 ml of dH2O to use later in the reaction, and in a moment of confusion I added them both to the flask. I don't want to talk about it.
White smoke was generated when the HCl was added, and the flask was put into a heating mantle in a fume hood.
Temp was raised to 115 C and kept there for 100 mins. When the heat was turned off and the temperature began to decrease, white precipitate was formed in the solution. PH was checked: 2.
The flask was then kept on an ice bath with stirring for 2 hours, before the precipitate was vacuum filtered and dried.
Yield: 17.3 g of white, sparkly crystals, which should be like 64% of theory. Melting point 192-194, to my utter joy.

2. The intermediate N-phtaloyl glutamic acid from above was mixed with 15.3 grams of thiourea in the same 3-necked flask.
50 ml of DMF was added.
The reaction mixture was heated to 167 c and refluxed at this temperature for 1 hour. The smell of sulphur from the thiourea mixed with the smell of DMF degrading to dimethylamine was really something.
Heating was turned off, and at 110 C 60 ml:s of dH2O was added and refluxed for another 30 minutes.
After cooling, the flask was transferred to an ice bath and kept there under stirring for another 30 minutes, after which the flask was refrigirated for about an hour.
The greyish-pink precipitate was vacuum filtered and washed with 60 ml of dH2O, then refluxed with 60 ml ethanol for about 20 minutes.
Filtered again, wsshed again with ethanol and water, and then dried. It was now perfectly white and sparkly.
Yield: 12.5 grams.

So I ran the first reaction in a strongly acidic solution by mistake and I was afraid I had ruined it, but the melting point checked out. The second reaction was textbook though, except for not recrystallising from DMF. The resulting sparkly, free-flowing pristine white powder seemed clean enough though.

Bioassay was made with 400 mg:s but gave no noticeable effect. So maybe I messed it up anyway?
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[*] posted on 24-10-2022 at 07:55


My take on the failure to produce a bioactive end product is that I'm actually looking at a crystal mix predominately consisting of phtalamide. I performed a recrystallisation from DMF which gave me 9.5 g:s in return, but bioassay failed again.

The melting point of phtlamide is like for thalidomide a good bit over 200 C (238 for phtalamide, 270 for thalidomide). I haven't tried the melting point yet. It's a bit of a hassle for me to do that with these temperatures since I don't have a melting point apparatus yet. But I'll get around to it.

I'm planning a second recrystallisation from DMF, and this time basify the solution even more with ammonia to dissolve the phtalamide. We'll see what my yield will be from that. Probably catastrophic, but right now I just want to get something functional out of this.

If that doesn't work, I have to run with the suspicion that my self-synthesised glutamic acid is faulty somehow. Possibly also the pyridine. In that case, I will revisit this synth with confirmed, lab grade reagents.

I will make this work.

Also, out of curiosity: how many of you who tried this reaction did a bioassay or a melting point determination of your final yield?

[Edited on 20222222/10/25 by DocX]
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[*] posted on 15-11-2022 at 09:26


I will eventually try making some thalidomide, i have all needed reagents except the glutamic acid or glutamine.
But i do have some food-grade monosodium glutamate from the asian store.
I could try either the lower yielding first method or the second method using acetic anhydride or thionyl chloride.

I like DocX´s method above, did you try it again and got it to work?
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[*] posted on 18-11-2022 at 12:21


No, I haven't gotten round to it yet. I'm waiting for lab grade reagents to try and exclude all the possible impure or faulty ones.

I did try to clean the product I have several times through recrystallisation from DMF, but to no avail.

Also, next time I'll go back to the original patent method using ammonium acetate as a nitrogen donor. I figure it's best to go to the absolute basic and then work my way from there.

Pyridine + phtalic anhydride + L-glutamic acid in 115 C.
Then Phtaloyl Glutamate + ammonium acetate in PEG400 and a bit of DMF at 160-180 C to get the product. I'll probably run that reaction really long also, to get good conversion.

As soon as I get something functional out of this I can start elaborating for yield.

This would be an excellent point in life to start meddling with TLC, I guess.

[Edited on 20222222/11/19 by DocX]
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[*] posted on 21-1-2023 at 05:48
Preparation of N,N-phthaloylglutamic acid


I have attempted the solvent-free procedure detailed by Tsjerk, I have been successful in the preparation of thalidomide, although my yields were relatively low.

I have completed a write-up detailing the preparation of the N,N-phthaloylglutamic acid intermediate, it is attached as a PDF.

My yields were consistent with the 54% reported by Tsjerk.

The write-up for the preparation of thalidomide is on its way :)

Please let me know if I've made any mistakes, or anything, all comments welcome!

Thanks for reading :)

Attachment: Preparation of N,N-phthaloylglutamic acid by the solvent-free reaction of phthalic anhydride and L-glutamic acid.pdf (52kB)
This file has been downloaded 18 times

[Edited on 21-1-2023 by SplendidAcylation]
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[*] posted on 23-1-2023 at 12:50


Very nicely done, SplendidAcylation, good work!

And a good writeup as well with repeated experiments.
Only thing i missed was the final step, you should have included it in the writeup.
But anyway, very nice.

Did you use thiourea in the microwave for the last step as in the paper "Microwave Promoted Synthesis of a Rehabilitated Drug: Thalidomide"?
Also in the paper they use this workup:
The crude RM after microwave irradiation was dissolved in THF and purified by column chromatography on silica gel (THF-hexane, 1:1) to afford a solid product of (±)-thalidomide (Yield 85%).

Did you use same workup with the column or some other way?
Also, are a fumehood required at this small scale?

I will try repeat your experiment and maybe increase the scale somewhat.
I really like to try a microwave for a reaction and this is the perfect experiment.

Attachment: Microwave Promoted Synthesis of a Rehabilitated Drug - Thalidomide - seijas2001.pdf (31kB)
This file has been downloaded 10 times

[Edited on 2023-1-23 by Mateo_swe]
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[*] posted on 24-1-2023 at 03:36


Quote: Originally posted by Mateo_swe  
Very nicely done, SplendidAcylation, good work!

And a good writeup as well with repeated experiments.
Only thing i missed was the final step, you should have included it in the writeup.
But anyway, very nice.

Did you use thiourea in the microwave for the last step as in the paper "Microwave Promoted Synthesis of a Rehabilitated Drug: Thalidomide"?
Also in the paper they use this workup:
The crude RM after microwave irradiation was dissolved in THF and purified by column chromatography on silica gel (THF-hexane, 1:1) to afford a solid product of (±)-thalidomide (Yield 85%).

Did you use same workup with the column or some other way?
Also, are a fumehood required at this small scale?

I will try repeat your experiment and maybe increase the scale somewhat.
I really like to try a microwave for a reaction and this is the perfect experiment.



[Edited on 2023-1-23 by Mateo_swe]


Note: Since I wrote this message, I have completed the write-up, however, for continuity, I shall leave the message here anyway.

Thanks!
By " final step" do you mean the microwave synthesis of thalidomide?
I am doing a separate write-up on that, it isn't quite finished yet!

I shall just answer your questions quickly because you will see all the details in the upcoming write-up:

I used urea.
I didn't use the column, I think the product I obtained is fairly pure though.

You definitely don't need a fume-hood, you won't even notice the smell of ammonia at this scale, unless you put your nose up to the test-tube.

Edit: The thalidomide write-up is now complete! It is attached as a PDF.



[Edited on 24-1-2023 by SplendidAcylation]

Attachment: Microwave synthesis of thalidomide.pdf (61kB)
This file has been downloaded 15 times

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[*] posted on 25-1-2023 at 12:54


Very nice!

OK, you used urea and not thiourea.
Thiourea is said to give better yields, if you can get some.
Regarding the question if a fumehood is needed, i was thinking about thiourea possible could make it smell a bit, especially if pyridine solvent were to be tried.
I think i can try this without a fumehood even if thiourea is used, its so small scale.
And i can make a quickfix fume extractor.

I wonder a bit about your yields though, i dont get how you calculated.
In the paper you write 35.5%, 20.0% and 26.7% yields of thalidomide for experiment 1, 2 and 3.
Are those yields based on the N-phthaloylglutamic acid used?
You get more final product in last experiment 3 using less N-phthaloylglutamic acid than in experiment 1 but still get lower yield?

I get
Exp 1
3.9mmol N-phthaloylglutamic acid used, 0.31g(1.2mmol) thalidomide, 1.2/3.9=30.8% yield

Exp 2
3.7mmol N-phthaloylglutamic acid used, 0.25g(0.97mmol) thalidomide, 0.97/3.7=26.2% yield

Exp 1
3.4mmol N-phthaloylglutamic acid used, 0.45g(1.7mmol) thalidomide, 1.7/3.4=51.25% yield

Or do i calculate wrong?
Im a beginner at chemistry so that is a likely explanation.
I will add my experiment here also when its done.
Good work SA

Edit:
Ok i see i calculated on the crude yield, thats why i got better yields.
However, searching for thalidomide solubility i find
Sparingly soluble in methanol, ethanol, acetone, ethyl acetate, butyl acetate, glacial acetic acid.
Very soluble in DMF, dioxane, pyridine.
Practically insoluble in ether, chloroform, benzene.

Sparringly soluble in other alcoholes (no mention of iPrOH though) makes me wonder if another solvent would have been better to use for the purification step.
Maybee you got better yields than you think.

[Edited on 2023-1-25 by Mateo_swe]

[Edited on 2023-1-25 by Mateo_swe]
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[*] posted on 2-2-2023 at 03:48


Quote: Originally posted by Mateo_swe  
Very nice!

OK, you used urea and not thiourea.
Thiourea is said to give better yields, if you can get some.
Regarding the question if a fumehood is needed, i was thinking about thiourea possible could make it smell a bit, especially if pyridine solvent were to be tried.
I think i can try this without a fumehood even if thiourea is used, its so small scale.
And i can make a quickfix fume extractor.

I wonder a bit about your yields though, i dont get how you calculated.
In the paper you write 35.5%, 20.0% and 26.7% yields of thalidomide for experiment 1, 2 and 3.
Are those yields based on the N-phthaloylglutamic acid used?
You get more final product in last experiment 3 using less N-phthaloylglutamic acid than in experiment 1 but still get lower yield?

I get
Exp 1
3.9mmol N-phthaloylglutamic acid used, 0.31g(1.2mmol) thalidomide, 1.2/3.9=30.8% yield

Exp 2
3.7mmol N-phthaloylglutamic acid used, 0.25g(0.97mmol) thalidomide, 0.97/3.7=26.2% yield

Exp 1
3.4mmol N-phthaloylglutamic acid used, 0.45g(1.7mmol) thalidomide, 1.7/3.4=51.25% yield

Or do i calculate wrong?
Im a beginner at chemistry so that is a likely explanation.
I will add my experiment here also when its done.
Good work SA

Edit:
Ok i see i calculated on the crude yield, thats why i got better yields.
However, searching for thalidomide solubility i find
Sparingly soluble in methanol, ethanol, acetone, ethyl acetate, butyl acetate, glacial acetic acid.
Very soluble in DMF, dioxane, pyridine.
Practically insoluble in ether, chloroform, benzene.

Sparringly soluble in other alcoholes (no mention of iPrOH though) makes me wonder if another solvent would have been better to use for the purification step.
Maybee you got better yields than you think.

[Edited on 2023-1-25 by Mateo_swe]

[Edited on 2023-1-25 by Mateo_swe]



:)

Yes, although the yields using urea are supposed to be 63% which is still six times better than my yields! :(

Regarding the solubility in alcohol, yeah, there is a possibility that the isopropanol dissolved some of the product, however, I don't think so, because:

"These were filtered from suspension, washed twice with 2mL cold water, and dried, yielding 0.25g of off-white powder.
The crude product was extracted with 4g of boiling isopropanol; Once dried, the undissolved product weighed only ~50mg.
A second extraction with boiling isopropanol removed no further soluble impurities, as the undissolved product after the second extraction, upon drying, still weighed ~50mg."


If the product were significantly soluble in isopropanol, the weight would have decreased from 50mg rather than remain the same.

Of course, my scales aren't 100% accurate, so it's possible the weight might have dropped slightly! :)

I have been thinking a bit about ways to improve the yield...

It occurred to me that maybe a catalyst could be used to improve the yields; Boric acid is known to catalyze the amidation of carboxylic acids in a urea melt, which is essentially what we are doing here in this reaction, so maybe boric acid would act as a catalyst here too?

Who knows.

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